2. Academic Validation
  3. The voltage-gated sodium channel inhibitor, 4,9-anhydrotetrodotoxin, blocks human Nav1.1 in addition to Nav1.6

The voltage-gated sodium channel inhibitor, 4,9-anhydrotetrodotoxin, blocks human Nav1.1 in addition to Nav1.6

  • Neurosci Lett. 2020 Apr 17;724:134853. doi: 10.1016/j.neulet.2020.134853.
Nicholas Denomme 1,  April L Lukowski 2,  Jacob M Hull 3,  Margaret B Jameson 4,  Alexandra A Bouza 5,  Alison R H Narayan 6,  Lori L Isom 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, 48109 United States; Center for Consciousness Science, University of Michigan, Ann Arbor, Michigan, 48109 United States.
  • 2 Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan, 48109 United States; Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, 48109 United States.
  • 3 Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan, 48109 United States.
  • 4 Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, 48109 United States; Molecular and Cellular Pharmacology Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705 United States.
  • 5 Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, 48109 United States.
  • 6 Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan, 48109 United States; Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, 48109 United States; Department of Chemistry, University of Michigan, Ann Arbor, Michigan, 48109 United States.
  • 7 Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, 48109 United States; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, 48109 United States; Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan, 48109 United States; Department of Neurology, University of Michigan, Ann Arbor, Michigan, 48109 United States. Electronic address: lisom@umich.edu.
PMID: 32114117 DOI: 10.1016/j.neulet.2020.134853
Abstract

Voltage-gated sodium channels (VGSCs) are responsible for the initiation and propagation of action potentials in neurons. The human genome includes ten human VGSC α-subunit genes, SCN(X)A, encoding Nav1.1-1.9 plus Nax. To understand the unique role that each VGSC plays in normal and pathophysiological function in neural networks, compounds with high affinity and selectivity for specific VGSC subtypes are required. Toward that goal, a structural analog of the VGSC pore blocker tetrodotoxin, 4,9-anhydrotetrodotoxin (4,9-ah-TTX), has been reported to be more selective in blocking Na+ current mediated by Nav1.6 than other TTX-sensitive VGSCs, including Nav1.2, Nav1.3, Nav1.4, and Nav1.7. While SCN1A, encoding Nav1.1, has been implicated in several neurological diseases, the effects of 4,9-ah-TTX on Nav1.1-mediated Na+ current have not been tested. Here, we compared the binding of 4,9-ah-TTX for human and mouse brain preparations, and the effects of 4,9-ah-TTX on human Nav1.1-, Nav1.3- and Nav1.6-mediated Na+ currents using the whole-cell patch clamp technique in heterologous cells. We show that, while 4,9-ah-TTX administration results in significant blockade of Nav1.6-mediated Na+ current in the nanomolar range, it also has significant effects on Nav1.1-mediated Na+ current. Thus, 4,9-ah-TTX is not a useful tool in identifying Nav1.6-specific effects in human brain networks.

Keywords

4,9-anhydrotetrodotoxin; Na(v)1.1; Voltage-gated sodium channels.

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